Novel Integrated Concepts for Preferential Crystallization

Driven by the policy of regulatory authorities such as US Food and Drug Administration and the EU Committee for Proprietary Medical Products the production of pure enantiomers is considerably increasing in several industrial branches, e.g. pharmaceutical, agrochemical, food industries as well as in cosmetic and fragrance industries [1]. An attractive process for gaining pure enantiomers from racemic mixtures is the so-called preferential crystallization [2-4]. The principle of this batch process is quite simple: the tank is filled with a supersaturated solution of the racemate (Ep+Ec as 50%:50% mixture). After addition of homochiral seeds (e.g. Ep) merely Ep is crystallizing within a limited time period. In order to gain this enantiomer as a product of high purity, the process must be stopped before the undesired counter-enantiomer occurs [3]. During this batch crystallization, the concentration of the desired enantiomer in the solution is decreasing, whereas the concentration of the counter-enantiomer remains constant. This phenomenon leads to an arrangement which might provide a better performance where two crystallizers are coupled via the liquid phase, i.e. the crystal free mother-liquor is exchanged between these two vessels. Because of this exchange, the liquid phase shows a higher overall concentration of the preferred enantiomer in that vessel in which the preferred enantiomer was seeded. The supersaturation level which corresponds to the crystallization driving force is higher during the whole process in comparison to the case without an exchange (decoupled simple batch mode). Additionally, the concentration of the counter-enantiomer in the liquid phase for each of the vessels decreases. For the borderline case of infinite exchange flow rate racemic composition is reached in the fluid phase of both vessels. The described effect of decreasing the counter-enantiomer concentration in that crystallizer in which the preferred enantiomer shall be gained makes the probability for primary nucleation lower. This corresponds to higher product purity at the end of the process and enhances also the productivity. This more attractive and effective operation mode using two batch crystallizers coupled via their liquid phases has been investigated theoretically and experimentally for the amino acid threonine in water [5-7]. The influence of specific process parameters, like e.g. the size distribution and the mass of the seeds, and different temperature profiles has been analyzed. The effect of racemization by exchanging the fluid phase allows the specific manipulation of concentration profiles and seems to be a suitable lever for process intensification on the apparatus level. Similar manipulation of the concentration profiles during the crystallization process can be also realized on molecular level if the racemization is achieved by an enzymatic reaction in which an excess of the counter-enantiomer in the liquid phase is transformed to the preferred one [8, 9]. By coupling crystallization (for conglomerate sys-tems) and racemization (for conversion of the unwanted enantiomer) expected theoretical yield of a pure enantiomer can lead up to 100%. Our goal is to develop a comprehensive study for each operating unit and their subsequent integration in a hybrid process. As a model component for the investigation, the amino acid asparagine in water has been chosen. The first configuration will be usually applied if there is a need for both enantiomers in pure form (with yields up to 50% for each enantiomer), whereas the second configuration provides just one enantiomer with very high yield (up to 100%). These different configurations for productivity enhancement with regard to preferential crystallization will be presented in this contribution. [1] CANER, H.; GRONER, E.; LEVY, L.; AGRANAT, I. (2004): Trends in the development of chiral drugs. Drug Discovery Today. 9 (3), 105-110 [2] JACQUES, J.; COLLET, A.; WILEN, S.H. (1994): Enantiomers, racemates and resolutions. Krieger, Malabar [3] ELSNER, M.P., FERNÁNDEZ MENÉNDEZ, D., ALONSO MUSLERA, E., SEIDEL-MORGENSTERN, A. (2005): Experimental study and simplified mathematical description of preferential crystallization. Chirality 17 (S1), S183-S195 [4] LORENZ, H., PERLBERG, A., SAPOUNDJIEV, D., ELSNER, M.P., SEIDEL-MORGENSTERN, A., (2006): Crystallization of enantiomers. Chem. Eng. and Proc. 45(10), 863-873 [5] ELSNER, M.P.; ZIOMEK, G.; SEIDEL-MORGENSTERN, A. (2007): Simultaneous preferential crystallization in a coupled, batch operation mode. Part I: Theoretical analysis and optimization. Chem. Eng. Sci. 62 (17), 4760-4769 [6] ELSNER, M.P.; ZIOMEK, G.; SEIDEL-MORGENSTERN, A. (2008): Efficient separation of enantiomers by preferential crystallization in two coupled vessels. AIChE Journal (submitted) [7] ZIOMEK, G.; ELSNER, M.P.; SEIDEL-MORGENSTERN, A. (2008): Simultaneous preferential crystallization in a coupled, batch operation mode – Part II: Experimental investigations. Chem. Eng. Sci. (in preparation) [8] LÜTZ, S.; WANDREY, C.; SEIDEL-MORGENSTERN, A.; ELSNER, M.P. (2006): Verfahren zur Herstellung chiraler Substanzen durch selektive Kristallisation unterstützt durch eine enzymatische Racemisierungsreaktion. DE 10 2006 013 725.6 (24.03.2006) [9] WÜRGES, K.; PETRUSEVSKA, K.; SERCI, S.; WILHELM, S.; WANDREY, C.; SEIDEL-MORGENSTERN, A.; ELSNER, M.P.; LÜTZ, S. (2008): Enzyme-assisted physicochemical enantioseparation processes – part I: Production and characterization of a recombinant amino acid racemase. Journal of Molecular Catalysis B: Enzymatic (submitted) © 2008 American Institute of Chemical Engineers [accessed December 11, 2008